LYPLAL1 (lysophospholipase-like 1) is a palmitoyl thioesterase that catalyzes depalmitoylation of specific protein substrates, including cGAS and KCNMA1 1. The enzyme possesses a shallow active site that restricts substrate specificity to short-chain substrates, lacking phospholipase and triacylglycerol lipase activities 2. LYPLAL1 functions as a negative regulator of innate immunity by depalmitoylating cGAS, thereby preventing cGAS homodimerization and cyclic GMP-AMP synthase activity 1. This depalmitoylation mechanism is therapeutically relevant: inhibition of LYPLAL1 enhances cGAS-mediated immune responses and improves anti-tumor efficacy of PD-1 blockade 1. Metabolically, LYPLAL1 influences lipid homeostasis through esterase activity rather than depalmitoylase function in hepatocytes 3. Rare loss-of-function variants in LYPLAL1 associate with reduced liver steatosis and protection against metabolic dysfunction-associated steatotic liver disease (MASLD) 3. LYPLAL1 knockout females show reduced weight gain and adiposity on high-fat diets, revealing sex-specific metabolic effects 4. Additionally, LYPLAL1 variants influence facial morphology in Eurasian populations 5. Related long noncoding RNAs (LYPLAL1-AS1 and LYPLAL1-DT) regulate adipogenic differentiation and chemotherapy resistance, suggesting broader functional roles for the LYPLAL1 locus 6, 7.